Tick-borne encephalitis (TBE) is a neurological disease caused by Flaviviruses of the tick-borne encephalitis group and causes death in up to 60% of the individuals developing clinical symptoms. Survivors often show severe long-term neurological sequelae. In addition to natural infection via vector ticks in endemic areas, the highly infective viruses can be transmitted via food or in aerosolized form. Therefore, development of a TBE virus vaccine is a NIH high-priority biodefense project. Currently available commercial vaccines based on inactivated whole virus are not registered in the U.S., show considerable vaccination side-effects and do not provide complete protection against the more virulent Far-Eastern subtype. The specific goal of this project is to investigate the efficacy of recombinant subunit proteins used with clinically relevant adjuvants to achieve protection in the mouse model of TBE against both major subtypes of TBE viruses. Tested formulations will be single or combinations of antigens and selected modern adjuvants. Positive results will lead to multicomponent candidate vaccine testing in phase II also in a second animal model. A safe and efficacious vaccine based on recombinant subunit proteins would provide useful in protecting U.S. citizens from TBEV infection without the need of large-scale culture of highly infectious virus